Selective inhibition of MALT1 protease by phenothiazine derivatives

Abstract

The invention relates to a compound for use in treating a cancer, wherein the cancer depends on the proteolytic activity of the MALT1 protease, and wherein the compound has the general formula (I) wherein X is N or C; Y is S, O, SO 2 , SO, NH, CO, CH 2 , CH═CH, or CH 2 —CH 2 ; ( ) z is a C 1 -C 5 linear or branched alkyl chain; A is NR 3 R 4 , or OR 5 , or HET; R 1 and R 2 in each occurrence are independently selected from —H, —CH 3 , —OH, —OCH 3 , —SCH 3 , —F, —Cl, —CF 3 , —NH 2 , and —COOH; R 3 , R 4 , and R 5 are H, or C 1 -C 5 linear or branched alkyl groups, and HET is a heterocyclic ring of 5, 6, or 7 members, wherein the ring atoms can be C, O, N, or S, the ring can be saturated or aromatic, and the ring can be substituted with H or C 1 -C 5 linear or branched alkyl groups; or a pharmaceutically acceptable salt, prodrug, enantiomer, diastereomer, racemic mixture, crystalline form, amorphous form, unsolvated form or solvate of said compound. The compound of the invention may further be used in the treatment of MALT1-dependent immune diseases.

The invention claimed is: 
     
       1. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a cancer that is the activated B-cell subtype of diffuse-large B cell lymphoma or MALT lymphoma, comprising administering an effective amount of a compound having the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X is N; 
         Y is S; 
         ( ) z  is a C 1 -C 5  linear or branched alkyl chain; 
         A is NR 3 R 4 , or OR 5 , or HET; 
         R 1  and R 2  in each occurrence are independently selected from —H, —CH 3 , —OH, —OCH 3 , —SCH 3 , —F, —Cl, —CF 3 , —NH 2 , and —COOH; 
         R 3 , R 4 , and R 5  are H, or C 1 -C 5  linear or branched alkyl groups, and 
         HET is a heterocyclic ring of 5, 6, or 7 members, wherein the ring atoms can be C, O, N, or S, the ring can be saturated or aromatic, and the ring can be substituted with H or C 1 -C 5  linear or branched alkyl groups; or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       2. The method according to  claim 1 , wherein
 ( ) z  is a linear C 1 -C 5  alkyl chain 
 R 1  is —H; and 
 R 2  is —H or —SCH 3 . 
 
     
     
       3. The method according to  claim 2 , wherein A is HET and HET is a 5-membered to 7-membered carbocyclic ring which is interrupted with NR 3 . 
     
     
       4. The method according to  claim 2 , wherein A is NR 3 R 4  and R 3  is H or CH 3  and R 4  is —CH 3 . 
     
     
       5. The method according to  claim 2 , wherein A is NR 3 R 4 , wherein R 3  is CH 3 , R 4  is —CH 3 , —C 2 H 5 , or a C 3 -C 5  linear alkyl chain the chain of which may be interrupted by O, N or S and which forms a saturated ring with a carbon atom of ( ) z . 
     
     
       6. The method according to  claim 5 , wherein the saturated ring is a 5-membered to 7-membered carbocyclic ring which is interrupted with N. 
     
     
       7. The method according to  claim 3 , wherein A is HET and HET is N-Methylpiperidin-2-yl or N-Methylpiperidin-3-yl. 
     
     
       8. The method according to  claim 1 , wherein
 (a) Z=3, A is NR 3 R 4 , and R 3  and R 4  are —CH 3 ; 
 (b) Z=1 and A is N-methylpiperidin-3-yl; or 
 (c) Z=2 and A is N-methylpiperidin-2-yl. 
 
     
     
       9. The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       10. The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       11. The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       12. The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       13. A method for inhibiting the activity of the MALT1 protease in a human subject in need thereof, wherein said activity is connected to a disease selected from a cancer that is the activated B-cell subtype of diffuse-large B cell lymphoma or MALT lymphoma, comprising administering an effective amount of a compound having the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X is N; 
         Y is S; 
         ( ) z  is a C 1 -C 5  linear or branched alkyl chain; 
         A is NR 3 R 4 , or OR 5 , or HET; 
         R 1  and R 2  in each occurrence are independently selected from —H, —CH 3 , —OH, —OCH 3 , —SCH 3 , —F, —Cl, —CF 3 , —NH 2 , and —COOH; 
         R 3 , R 4 , and R 5  are H, or C 1 -C 5  linear or branched alkyl groups, and 
         HET is a heterocyclic ring of 5, 6, or 7 members, wherein the ring atoms can be C, O, N, or S, the ring can be saturated or aromatic, and the ring can be substituted with H or C 1 -C 5  linear or branched alkyl groups; or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       14. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a MALT1-dependent immune disease that is multiple sclerosis, psoriasis, or rheumatoid arthritis, comprising administering an effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       15. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a MALT1-dependent immune disease that is multiple sclerosis, psoriasis, or rheumatoid arthritis, comprising administering an effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       16. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a MALT1-dependent immune disease that is multiple sclerosis, psoriasis, or rheumatoid arthritis, comprising administering an effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or solvate of said compound. 
       
     
     
       17. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a MALT1-dependent immune disease that is multiple sclerosis, psoriasis, or rheumatoid arthritis, comprising administering an effective amount of a compound having the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X is N; 
         Y is S; 
         (i) ( ) z  is a C 3 -C 4  linear alkyl chain and A is NR 3 R 4  or OR 5 ; or; 
         (ii) ( ) z  is a C 1 -C 2  linear alkyl chain and A is HET 
         R 1  and R 2  in each occurrence are independently selected from —H, —CH 3 , —OH, —OCH 3 , —SCH 3 , —F, —Cl and —CF 3 ; 
         R 3 , R 4 , and R 5  are H, or C 1 -C 3  linear or branched alkyl groups, and 
         HET is a heterocyclic ring of 5, 6, or 7 members, wherein the ring atoms can be C, O or N, the ring includes at least 1 N atom, can be saturated or aromatic, and the ring can be substituted with H or C 1 -C 2  linear or branched alkyl groups; or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       18. A method for inhibiting the activity of the MALT1 protease in a human subject in need thereof, wherein said activity is connected to a disease selected from a MALT1-dependent immune disease that is multiple sclerosis, psoriasis, or rheumatoid arthritis, comprising administering an effective amount of a compound having the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X is N; 
         Y is S; 
         (i) ( ) z  is a C 3 -C 4  linear alkyl chain and A is NR 3 R 4  or OR 5 ; or; 
         (ii) ( ) z  is a C 1 -C 2  linear alkyl chain and A is HET 
         R 1  and R 2  in each occurrence are independently selected from —H, —CH 3 , —OH, —OCH 3 , —SCH 3 , —F, —Cl and —CF 3 ; 
         R 3 , R 4 , and R 5  are H, or C 1 -C 3  linear or branched alkyl groups, and 
         HET is a heterocyclic ring of 5, 6, or 7 members, wherein the ring atoms can be C, O or N, the ring includes at least 1 N atom, can be saturated or aromatic, and the ring can be substituted with H or C 1 -C 2  linear or branched alkyl groups; or 
         a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       19. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a cancer that is the activated B-cell subtype of diffuse-large B cell lymphoma or MALT lymphoma, comprising administering an effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       20. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a cancer that is the activated B-cell subtype of diffuse-large B cell lymphoma or MALT lymphoma, comprising administering an effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic mixture, or solvate of said compound. 
       
     
     
       21. A method for treating a disease that depends on the activity of the MALT1 protease in a human subject in need thereof, wherein said disease is selected from a cancer that is the activated B-cell subtype of diffuse-large B cell lymphoma or MALT lymphoma, comprising administering an effective amount of the compound 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or solvate of said compound.